Article Text

other Versions

Download PDFPDF
Causal associations of antioxidants with Alzheimer’s disease and cognitive function: a Mendelian randomisation study
  1. Jiao Wang1,
  2. Yingyue Huang1,
  3. Chunhua Bei2,
  4. Huiling Yang3,
  5. Zihong Lin4,
  6. Lin Xu1,5
  1. 1School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong, China
  2. 2School of Public Health, Guilin Medical University, Guilin, Guangxi, China
  3. 3Eastern-fusion Master Studio of Hezhou, Hezhou, China
  4. 4Hezhou Research Institute of Longevity Health Science, Hezhou, China
  5. 5School of Public Health, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China
  1. Correspondence to Professor Lin Xu, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong, China; xulin27{at}


Background Circulating antioxidants are associated with a lower risk of Alzheimer’s disease (AD) in observational studies, suggesting potential target areas for intervention. However, whether the associations are causal remains unclear. Here, we studied the causality between antioxidants and AD or cognitive function using two-sample Mendelian randomisation (MR).

Methods Single nucleotide polymorphisms strongly (p<5×10−8) associated with antioxidants (vitamin A, vitamin C, zinc, selenium, β-carotene and urate) and outcomes (AD, cognitive performance and reaction time) were obtained from the largest and most recent genome-wide association studies (GWAS). MR inverse variance weighting (IVW) and MR pleiotropy residual sum and outlier test (MR-PRESSO) were used for data analysis.

Results Higher genetically determined selenium level was associated with 5% higher risk of AD (OR 1.047, 95% CI 1.005 to 1.091, p=0.028) using IVW. Higher genetically determined urate level was associated with worse cognitive performance (β=−0.026, 95% CI −0.044 to −0.008, p=0.005) using MR-PRESSO. No association between the other antioxidants and AD, cognitive performance and reaction time was found. Similar results were found in the sensitivity analyses.

Conclusion Our results suggest that lifelong exposure to higher selenium may be associated with a higher risk of AD, and higher urate levels could be associated with worse cognitive performance. Further analyses using larger GWAS of antioxidants are warranted to confirm these observations. Our results suggest that caution is needed in the interpretation of traditional observational evidence on the neuroprotective effects of antioxidants.


Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • JW and YH are joint first authors.

  • Contributors JW, YYH, CB, HY, ZL and LX all have substantial contributions to the conception and design and to the interpretation of the data. JW and YYH analysed the data and drafted the article. LX, CB, HY and ZL revised it critically for important intellectual content. YYH is co-first author. LX acts as the guarantor. All authors contributed to the final approval of the paper.

  • Funding This work was funded by the National Natural Science Foundation of China (82373661 and 82103930) and the Natural Science Foundation of Guangdong (2022A1515011546). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.